Trauma causes approximately 150,000 deaths per year, and is the leading cause of death in the population between ages 1 to 44 in the United States. The resulting loss of productive life years exceeds that of any other disease, with estimated societal costs of >$450 billion annually. Most trauma deaths result from insufficient tissue perfusion due to excessive blood loss. Clinical management of trauma victims currently relies on massive and rapid infusion of fluids, to which a large number of such victims often do not respond. The development of effective strategies for resuscitation of severe traumatic blood loss therefore is critically needed. The market potential for hemorrhage treatment is estimated at >$10 billion/year in the US alone. We have recently discovered that vascular responsiveness to adrenomedullin (AM), a recently-discovered potent vasoactive peptide, decreases after hemorrhage in rats, which is markedly improved by its novel binding protein (i.e., AMBP-1). Treatment with rat AM plus AMBP-1 reduces tissue injury and inflammatory responses after hemorrhage and large volume resuscitation, suggesting that AM/AMBP-1 may be a beneficial treatment approach in human trauma. One obstacle hampering development of AM/AMBP-1 as a therapeutic agent for hemorrhagic shock is the potential immunogenicity of rat proteins in humans. It remains unknown, however, whether human AM plus human AMBP-1 is also beneficial and, if so, whether their administration with the reduced resuscitation fluid volume decreases mortality after hemorrhage. We therefore hypothesize that administration of human AM/AMBP-1, even with low volume resuscitation, improves survival after severe blood loss. The primary objective of this project, therefore, is to demonstrate the feasibility of further development of human AM/AMBP-1 as a novel therapeutic agent to reduce hemorrhage-induced organ injury, inflammation, and mortality in a rat model of hemorrhage. The proposed studies should provide useful feasibility information for further developing AM/AMBP-1 as an effective therapy for the treatment of hemorrhagic shock. Our ultimate goal (Phase IISBIR and beyond) is to develop the commercial utilization of human AM/AMBP-1 as a safe and effective resuscitation approach for the trauma victim with severe blood loss, especially for the use in combat casualty care at the far-forward battlefield setting.